STEVE
USDIN: American food and drug laws lurch from one scandal and tragedy to
another. I'm Steve Usdin on FDA's White Oak campus for an inside look at 152
years of fascinating history. Welcome to BioCentury This Week.

NARRATOR:
Connecting patients, scientists, innovators, and policymakers to the future of
medicine, BioCentury This Week.

STEVE
USDIN: Americans take it for granted that government ensures foods are safe and
medical products are safe and effective. But that wasn't always the case. FDA
started out during the Civil War as a single chemist with little authority. For
the next 50 years, there were few restrictions on what could be sold or claims
that could be made.

The
pattern's been consistent from the start. Opposition to government oversight,
then a tragedy or scandal leads to expansion of FDA's mission and power. The
first food and drug law was enacted in 1906 because of the work of two men.

One
dramatized dangerous food additives by poisoning government clerks. The other
wrote a book to make the case for a revolution but had a big impact because it
was revolting. I'm in FDA headquarters with FDA historian Dr. John Swann. John,
can you tell us, who was Harvey Wiley, and what was the Poison Squad?

DR.
JOHN SWANN: Well, Harvey Wiley is widely regarded as the father of the Food and
Drug Administration for good reason. He was the head of the Bureau of
Chemistry, our forerunner, at the time that the 1906 Food and Drugs Act was
passed. So Wiley came here as a well-recognized scientist, also a very
politically savvy individual.

One
of the things Wiley did to help illustrate the need for a law was a study of
the impact of preservatives on individuals. So he recruited volunteers from the
Bureau of Chemistry. In fact, there were many more volunteers than could
actually join the study. But rotating groups of 12 or so would conduct feeding
experiments.

They'd
have measured amounts of food. And then sprinkled in with that food would be
various preservatives, preservatives like formaldehyde, sodium benzoate, borax,
boric acid, and salicylic acid, which is recorded here in one of the notebooks
of the poison squad.

STEVE
USDIN: So he would measure the things out on a scale like this and then keep
meticulous records of what happened when he poisoned these government clerks.

DR.
JOHN SWANN: Well, poison might be a strong word, but certainly the public
understood it to be poisoning. And that's one of the reasons why the Poison Squad
attracted so much attention by the press and others.

So
they found out that it actually, as the dosages of the preservatives got
greater, the individuals would suffer headaches and nausea and so on. So it
actually kind of changed minds, even Harvey Wiley's mind. He was willing to
allow some preservatives. But after this study, he felt that preservatives were
a real problem.

STEVE
USDIN: So the other thing that happened around this time was that Upton
Sinclair wrote a book that he intended to provoke a socialist revolution in
America. And instead, it had quite a different effect. What was it?

DR.
JOHN SWANN: It did. The Jungle actually was intended to be a novel, as
you said, that portrayed the importance of socialist ideals to bring the
country up from where it was. But this tale of an immigrant family from Lithuania
who settled in Chicago, went to work in the meat packing industry, really told
a tale of hazards in the food marketplace. Because this was a very carefully
researched novel. And Sinclair portrayed it quite accurately, even when people
were falling into vats of lard and being canned with the products.

STEVE
USDIN: So that led to the passage of the Pure Food Act. What was in that act?
What did it do? What was its effect?

DR.
JOHN SWANN: Essentially the Pure Food and Drugs Act of 1906 outlawed adulterated
and misbranded foods and drugs. Drugs had to abide by standards, and certain
ingredients in products like heroin and cocaine and alcohol had to be labeled,
but there wasn't widespread labeling.

Foods
certainly had to keep certain ingredients out of foods, things that would
conceal foods, or substitute foods, or serve as health hazards. But it was a
labeling law. It was in many ways the pinnacle of the progressive era. But it
did have shortcomings.

STEVE
USDIN: So to illustrate those shortcomings and to warn the American public and
get publicity, the administration created what they called the Chamber of
Horrors. Very briefly, what was that?

DR.
JOHN SWANN: Well, the Chamber of Horrors was essentially a traveling exhibit
that the FDA put together to alert the public, alert the press and members of
Congress too about why a new law was needed. They used various examples of
products that were on the market legally that were literally killing people or
harming people. And so this kind of mayhem as portrayed in the Chamber of
Horrors really attracted a lot of attention.

STEVE
USDIN: And the Chamber of Horrors got a little bit of attention, but what
really grabbed the public's attention was the first real serious tragedy
involving a drug in the United States. What was that?

DR.
JOHN SWANN: Well, that involved a drug called elixir sulfanilamide, which was
an oral preparation of a recently discovered wonder drug called sulfanilamide.
And the company that manufactured it had not done any testing whatsoever other
than testing it for taste and color and so on. There was nothing in the law
that required them to do any testing of a drug before it went on the
marketplace.

They
introduced it in 1937, and within days the body count started rising.
Originally these were reported to the American Medical Association then to FDA.
But children, others were dying from this preparation because it contained as a
solvent diethylene glycol, which is a chemical analogue --

STEVE
USDIN: Antifreeze

DR.
JOHN SWANN: -- of antifreeze, exactly.

STEVE
USDIN: So about 106 people died from that. And that prompted, that kind of gave
the push that was needed to get new legislation through Congress, didn't it?

DR.
JOHN SWANN: It did. There were bills introduced after Franklin Roosevelt was
elected, but those bills were going nowhere since 1933. But because of the
public outcry over this therapeutic disaster, yes, the law did eventually pass,
and President Roosevelt signed it in 1938.

STEVE
USDIN: And that was the Food, Drug, and Cosmetic Act.

DR.
JOHN SWANN: That's right.

STEVE
USDIN: The first real regulation of food and drug.

DR.
JOHN SWANN: It was. It's the law that we still operate under today, amended
many times, of course. But it lent many additional protections to foods, to
drugs as well, and also brought new products under the law as well, cosmetics
and medical devices, for example.

STEVE
USDIN: World War II stimulated the development of the modern pharmaceutical
industry, including the first antibiotics. Congress gave FDA the job of making
sure the new drugs were safe.

NARRATOR:
You're watching BioCentury This Week.

SEGMENT 2

NARRATOR:
In 1959, Senator Estes Kefauver held a series of highly publicized hearings
highlighting criticisms of the pharmaceutical industry. The hearings made
headlines, but drug company lobbying made it impossible to pass legislation.
Then a young FDA scientist prevented a disaster, prompting Congress to enact a
law giving FDA unprecedented authority to regulate drugs.

STEVE
USDIN: So John, the Kefauver hearings provoked a lot of public opinion, a lot
of public reaction. But they didn't get a law passed. What really had to happen
to get the law passed was a tragedy overseas and a near tragedy in the United
States. What was that?

JOHN
SWANN: Well this, as you said, the hearings produced a bill, but the bill went
nowhere. There was a lot of resistance to that by the industry, by a lot of the
research community. But while this was in play, there was an application that
came into FDA, September 1960 for a drug called thalidomide.

And
this was a drug that had been on the market since 1956 in Germany and in other
countries around the world. Here, it was under review by medical officer
Francis Kelsey, who was quite appalled by the nature of the evidence that came
in with the application. More testimonial than anything. And particular for a
sedative, she was looking for chronic toxicity data. That was not there. So
there were a lot of problems with this application.

So
while this is going on, the drug is on the market -- Germany, England,
Australia, many countries around the world. And there begins to be a clustering
of very rare but very severe birth defects. And it took a long time, but a
couple researchers in Germany and in Australia finally linked this problem to
that drug, thalidomide. And the drug, if given in a certain part of the
pregnancy, could cause these very severe defects.

STEVE
USDIN: So Francis Kelsey, she was given an award by President Kennedy, and it
propelled this legislation through Congress. People were so appalled that we
almost had this kind of horrific tragedy in the United States. The 1962
amendments, what were they? What did they do?

JOHN
SWANN: Well, the 1962 amendments basically established the gold standard for
drug review for the rest of the world. So what they did was, they included
effectiveness as a requirement for pre-market approval by FDA, as well as drug
safety. They also required a high level of evidence, for any application, for
both safety and effectiveness.

So
it had to be substantial evidence, as seen in a controlled clinical trial
conducted by those who were qualified to conduct trials. It really changed the
way that we regulate drugs, and that's because we had a near miss in this
country.

STEVE
USDIN: And the other thing it does -- one of the other things that it does --
is that it requires companies report adverse events after something's on the
market to FDA, right?

JOHN
SWANN: That's correct. Any kind of effect like this had to be reported to FDA
from that point forward.

STEVE
USDIN: So it really set the standard. Like you said, it set the gold standard.
It created what we think of today as the right way to regulate drugs in the
United States and around the world.

JOHN
SWANN: That's correct.

STEVE
USDIN: And it was all a result of barely missing this tragedy.

JOHN
SWANN: Yeah. Barely is the right word, because there were some cases of this
birth defect in this country, but that's because the drug was widely
disseminated by the sponsor as a so-called investigational drug. There were
over 20,000 patients that had taken this drug. There were over 1,200 physicians
that were given this drug by the company. FDA was not aware of this. There were
over 600 pregnant women that took it, and it's a wonder that there were only 17
cases of this severe birth defect in this country.

STEVE
USDIN: So that was one of the other things, one of the reasons why it propelled
this legislation to control clinical trials, right? So that people -- drug
companies couldn't just give drugs out willy nilly and claim that it was a
trial?

JOHN
SWANN: Well that's right. One could argue this in many ways, but the fact that
it impelled companies to provide robust scientific evidence to support the
safety and effectiveness claims is in many ways the hallmark of this
legislation.

NARRATOR:
In the 1980s, a determined mother, a congressman, and a Hollywood celebrity
teamed up to persuade Congress to create incentives for drug companies to
develop products for very small markets. Millions have benefited.

ABBEY
MEYERS: And somebody said, Abbey, there's a man on the phone, and he says his
name is Maurice Klugman, and he's the brother of Jack Klugman. And he was a
producer of the Quincy Show. And he said, I think that my brother should make a
show about this topic. The law is so effective because it was an economic
problem, and we found an economic solution to solve the problem.

SEGMENT 3

NARRATOR:
Back to BioCentury This Week.

STEVE
USDIN: So John, one of the things -- you know, Harvey Wiley and the Poison
Squad. The Jungle, thalidomide, they all showed that kind of having a
big public attention on something was what was needed for getting change in the
law and FDA regulations. The next kind of big change that I wanted to talk
about is the Orphan Drug Act. And that one actually involved celebrity, and a
member of Congress, and a mother working together, didn't it?

JOHN
SWANN: Well, it did. The Orphan Drug Act is in many ways a continuation of this
rising public interest in drug laws, drug regulations, and patient issues,
patient protections. And it really showed that brought together, a variety of
interests could really make a change. And in this case, you mentioned, for
example, an actor.

STEVE
USDIN: Jack Klugman.

JOHN
SWANN: That's right. Of course, this was a grassroots organization started by
many families of those who are affected by rare disorders, those affecting just
a tiny population compared to other diseases. And before then, they were really
neglected. That's where the term, of course, orphan diseases comes from. But
because of the involvement of this community, I think Congress finally took
note of this. Henry Waxman, among others.

STEVE
USDIN: So you say you had Henry Waxman holding hearings, you had Abbey Meyers,
who was a mother with a child with a rare disease. And then they brought Jack
Klugman in, who actually made two television shows about rare diseases that
really propelled the issue through Congress.

What
did it do? What did the Orphan Drug Act do, and why was it important?

JOHN
SWANN: Well what the Orphan Drug act did was provide incentives to companies to
research and produce drugs for these small patient populations. And under the
law, these populations were defined as those under 200,000 patients. And it
provided, for example, seven years of market exclusivity in the event that the
compound was otherwise not patentable.

It
also provided input from FDA in the design of clinical trials to help research
this. And it provided tax write offs for the research involved. So it did
provide a number of incentives.

STEVE
USDIN: And hundreds, literally hundreds of drugs have been approved that
wouldn't have been approved without it. Here's two examples. These are the
first two, right?

JOHN
SWANN: Right. Hemin and Chenodiol. Chenodiol was used for gallstones in
patients who, for one reason or another, couldn't subject themselves to
surgery. And Hemin was used in cases of acute Porphyria, blood disease. So
these were the first. But you're right, there have been over 400 orphan drugs
approved by FDA. And literally millions of patients have benefited because of
this law.

STEVE
USDIN: So the great tragedy that affected the United States after the Orphan
Drug Act was the AIDS epidemic. And that was kind of brought literally to FDA's
gates, wasn't it?

JOHN
SWANN: That's right. And this was actually just about a year before I came to
the agency, but at the headquarters in the Parklawn building in Rockville,
there was a major demonstration led by the AIDS coalition to unleash power. And
they basically surrounded the building, essentially shut it down. And the
reason is, they were clamoring. Those protesting -- patients, families of
patients, supporters-- were clamoring for greater access to experimental drugs.

And
in the end, they did get a seat at the table to help develop greater access to
investigational medicines.

STEVE
USDIN: And one of the things that came out of that was accelerated approval,
which really basically made it possible to develop AIDS drugs. It saved and
extended millions of lives around the world.

JOHN
SWANN: Right. From about 1987, for the next decade or so, there were a variety
of means by which drugs -- access to experimental drugs was increased, or
approval was accelerated. Treatment INDs were started in 1987, where in cases
of serious or life threatening diseases, patients could get access to
experimental drugs, for example.

STEVE
USDIN: So that activism really changed history. It changed FDA law, and it
changed the way that patients really interact with and think about experimental
drugs and the drug development process.

JOHN
SWANN: It did. The evidence of the changes and regulations on accelerated
approval and enhanced access speaks for itself.

STEVE
USDIN: John, the 1938 law gave FDA the authority to regulate devices. And it
spent a lot of its time tracking down quack devices like Wilheim Reich's orgone
accumulator, things like that. We've got some in front of us here. Can you talk
about them?

JOHN
SWANN: Sure. It was the emphasis of the agency, at least in the initial years
and a couple -- two or three decades after the law was passed -- to focus on
these kind of fraudulent devices, at least until regular medical devices came
along a little bit later. But here we see some examples over the decades of
different devices that the FDA moved against.

Here
on our right is the Zerret applicator. This was developed by William Ferguson
in the 1940s who had the idea that particularly powerful rays came down from
the heavens in the shape of a z. And that's how he came up with the Zerret
applicator. And inside that device is water impregnated with z rays. So this
became Zerret water. And if you held this in your hands, it would basically
cure pretty much anything.

If
you wanted to lose weight, gain weight. If you had a variety of medical
conditions, this device was for you.

STEVE
USDIN: And the theme about losing weight is a common one. This is what? The
Relax-a-Cizor which they claimed that also would help you lose weight.

JOHN
SWANN: The Relax-a-Cizor, right. That had been around since the 1940s,
originally distributed through salons in LA. But eventually it was distributed
nationwide. And in the 1960s, the FDA tried to move against this device, which
promoted weight loss, muscle gain in particular places using these pads applied
to different parts of the body. That's where you could have spot weight
reduction. But the FDA, after a study done at Duke, found that this actually
was quite harmful to particular patients. For example, those who suffered
epilepsy and other conditions.

So
we actually moved against this device and had it taken off the market. But
because there were so many -- there are 400,000 that had already been sold, FDA
distributed this poster to post offices around the country warning the public
about the Relax-a-Cizor.

STEVE
USDIN: And what do we have here?

JOHN
SWANN: In front, we have -- well, the device with the bulb is called the turbo
bust. There were a host of bust enhancers that were distributed, particularly
in the 1950s, and this is one example. The user would basically create a vacuum
and allegedly increase the bust size using this device.

STEVE
USDIN: And it was a bust, right? It didn't actually work.

JOHN
SWANN: That's right, it was a bust. And it's also worth mentioning another
device here called the Crampeze. Now some of these devices have very intricate
ideas and theories behind their use. The Crampeze was a lot more
straightforward. If you breathed into it, you could relieve yourself of cramps --
in the legs and so on.

STEVE
USDIN: And that worked about as well as all these other ones, right?

JOHN
SWANN: That's right

NARRATOR:
The 9/11 attacks were followed by anthrax attacks that killed 5, sickened 22,
and terrorized the nation. They also led to the Public Security and
Bioterrerosim Preparedness and Response act of 2002.

SEGMENT 4

NARRATOR:
In 2004, the withdrawal of a widely used drug set off a firestorm of criticism
about FDA's regulation of drug safety. The response included legislation and
tougher oversight that raised hurdles for drug development.

STEVE
USDIN: So John, the withdrawal of Vioxx in 2004 was really a turning point for
FDA and for the country, wasn't it?

JOHN
SWANN: It was. Vioxx was approved by FDA for osteoarthritis and acute pain in
1999, but it soon showed itself to have serious cardiovascular events,
certainly compared to other non-steroidal anti-inflammatory drugs. So
eventually, these reactions became more pronounced through other studies. And
in 2004, as you said, Merck did withdraw the drug from the market.

STEVE
USDIN: And that created a firestorm of criticism of the FDA. In a sense in the
Congress, and in a sense in the country that the FDA wasn't doing its job in
keeping potentially unsafe drugs off the market.

JOHN
SWANN: Well that was a concern that was voiced by members of Congress, among
others. And in fact, there was an Institute of Medicine study that came out in
2006 making a number of recommendations about drug safety and how FDA should be
more attentive to drug safety issues.

STEVE
USDIN: And that that led to the FDA Modernization Act, which really gave more
teeth to the FDA and more responsibility for ensuring safety of drugs, didn't
it?

JOHN
SWANN: It did. I mean, the Modernization Act, of course, was a very broad law.
It codified many elements that were already in place in terms of expediting
drug approval, of FDA's discretion with certain requirements for evidence. But
yes, it did look at a number of issues, including drug safety.

And
also, there were a couple elements of this that were brand new, one of which
was making off-label drug information legitimate, at least under the law. And
it also addressed devices as well, medical devices. And it allowed companies to
get outside external review of Class I and Class II select medical devices.

STEVE
USDIN: The ones that were less risky?

JOHN
SWANN: That's right.

STEVE
USDIN: So one of the other things that happened is that FDA, as a result of
Vioxx and congressional criticism, it kind of upped the threshold for approving
drugs. And it actually took actions against some drugs that were on the market.
Avandia was a classic case. There was another antibiotic called Ketek. And
later there was a sense that it had kind of gone too far. And that led to
FDASIA, the Food and Drug Safety and Innovation Act.

JOHN
SWANN: That's right. And by the way, it's probably worth mentioning that a lot
of these laws are passed in accord with the sunset provisions of the
Prescription Drug User Fee Act. And these are sort of every five year
provisions. And that's sort of a new way that regulation is done, or at least
drug regulation is done, as those sunset laws set in.

So
right, the FDA safety and innovation act came along and made many changes.
Among them, probably worth noting, foreign drug manufacturers are supplying the
vast majority of active pharmaceutical ingredients. So that law requires FDA to
take a much more active stance in inspecting those establishments, because of
problems with Heparin, for example.

STEVE
USDIN: And that brings us up to the present. Things we've talked about on this
show a lot. We've talked about the Breakthrough Drug Act, we've talked about
inspections of foreign drug facilities. I'm wondering -- we've just got a little
bit of time left today. Kind of thinking back on this whole arc of history,
starting with Harvey Wiley and going to the Food and Drug Safety and Innovation
Act, what does all this bring to your mind?

JOHN
SWANN: Well, if nothing else, hopefully we understand that so many things have
a role in the way we regulate products that the citizens take. Many people --
many individuals, many associations, institutions -- have a role. The press
does. The courts have, over the years. Technology has changed things. Certainly
therapeutic disasters have made a difference, but also it's been a response to
technology changes.

STEVE
USDIN: And to social changes.

JOHN
SWANN: Absolutely. Social changes have. The role of the public in their taking
on more responsibility for their health and everything that goes into that.
We've seen that constantly over the span of the last century plus, but
particularly within the last 30, 40 years.

STEVE
USDIN: Thanks a lot, John, for this kind of galloping look at the history of
the FDA. If you have any thoughts about today's show, you can tweet about them.
Use the hashtag #BioCenturyTV. Thanks for watching. I'll see you next week.